Serotonin and dopamine are neurotransmitters that play critical roles in human behavioral disorders and drug abuse. Deficits in serotonin signal transduction result in a plethora of behavioral disorders, including bulimia, post-traumatic stress disorder, depression, and suicide. Nearly all drugs of abuse affect dopaminergic neurotransmission. This proposal details a plan to study serotonin and dopamine signaling in the genetically tractable nematode Caenorhabditis elegans using genetic and behavioral approaches, and using chemosensation as a functional assay. The long term goals of the proposed research are to elucidate the mechanisms of serotonin and dopamine signaling, and to use C. elegans as a tool to identify novel genes and cellular mechanisms in these signaling pathways that may be applied to drug discovery for debilitating mental disorders and prevention of drug abuse. To identify novel genes involved in serotonin regulation of chemosensation, a yeast two hybrid screen will be carried out to identify interactors with the novel serotonin effector GPA-11. The expression pattern of genes identified in this screen will be characterized using GFP reporter constructs, and their function will be analyzed using genetic mutants and RNA interference in chemosensation assays. Two screens will be used to identify genes involved in dopamine regulation of chemosensation. First, a directed screen of candidate genes will be carried out, using a panel of pre-existing loss of function mutants defective in G(alpha) proteins and metabotropic dopamine receptors. Second, an unbiased forward genetic screen will be carried out to identify genes required for dopamine signaling, using a dopamine-decreased sensitized background. In addition to genetic screens, laser microsurgery of C. elegans neurons will be used to elucidate the cellular focus of dopamine action. Relevance: Mental and behavioral disorders have an immense impact on the quality of human life. By studying serotonin and dopamine, further insight will be gained into the underlying problems of these disorders and will one day lead to safe and effective therapies [unreadable] [unreadable]